The use of radioactive materials in diagnostic medicine has been readily accepted because these procedures are safe, minimally invasive, cost effective, and they provide unique structural and/or functional information that is otherwise unavailable to the clinician. The utility of nuclear medicine is reflected by the more than 13 million diagnostic procedures that are performed each year in the U.S. alone, which translates to approximately one of every four admitted hospital patients receiving a nuclear medical procedure. [See, Adelstein, et al., Eds., Isotopes for Medicine and the Life Sciences; National Academy Press: Washington, D.C., 1995; Wagner et al., “Expert Panel: Forecast Future Demand for Medical Isotopes”, Department of Energy, Office of Nuclear Energy, Science, and Technology; 1999; and Bond et al., Ind. Eng. Chem. Res. 2000, 39:3130-3134.]
The use of radiation in disease treatment has long been practiced, with the mainstay external beam radiation therapy now giving way to more targeted delivery mechanisms. By example, sealed-source implants containing palladium-103 or iodine-125 are employed in the brachytherapeutic treatment of prostate cancer; samarium-153 or rhenium-188 are conjugated to diphosphonate-based biolocalization agents that concentrate at metastases in the palliation of bone cancer pain; and radioimmunotherapy (RIT) relies on radionuclide conjugation to peptides, proteins, or antibodies that selectively concentrate at the disease site whereby radioactive decay imparts cytotoxic effects.
Radioimmunotherapy represents the most selective means of delivering a cytotoxic dose of radiation to diseased cells while sparing healthy tissue, [see, Geerlings et al., U.S. Pat. No. 5,246,691, 1993; Whitlock et al., Ind. Eng. Chem. Res. 2000, 39:3135-3139; Hassfjell et al., Chem. Rev. 2001, 101:2019-2036; Imam, Int. J. Radiation Oncology Biol. Phys. 2001, 51:271-278; and McDevitt et al., Science 2001, 294:1537-1540] and the plethora of information about disease genesis and function arising from the human genome project is expected to propel RIT into a leading treatment for micrometastatic carcinoma (e.g., lymphomas and leukemias) and small- to medium-sized tumors.
Candidate radionuclides for RIT typically have radioactive half-lives in the range of 30 minutes to several days, coordination chemistry that permits attachment to biolocalization agents, and a high linear energy transfer (LET). The LET is defined as the energy deposited in matter per unit path length of a charged particle, [see, Choppin et al., Nuclear Chemistry: Theory and Applications; Pergamon Press: Oxford, 1980] and the LET of α-particles is substantially greater than β1−-particles. By example, α-particles having a mean energy in the 5-9 MeV range typically expend their energy within about 50-90 μm in tissue, which corresponds to several cell diameters. The lower LET β1−-particles having energies of about 0.5-2.5 MeV can travel up to 10,000 μm in tissue, and the low LET requires as many as 100,000 β1−-emissions at the cell surface to afford a 99.99 percent cell-kill probability. For a single α-particle at the cellular surface, however, the considerably higher LET gives a 20-40 percent probability of inducing cytotoxicity as the lone α-particle traverses the nucleus. [See, Hassfjell et al., Chem. Rev. 2001, 101:2019-2036.]
Because of their use in medical procedures, various governing bodies [e.g., the U.S. Food and Drug Administration (FDA)] mandate rigorous purity requirements for radiopharmaceuticals. Regulations governing the use of radionuclides for therapeutic applications are even more stringent, and such strict regulation is not unexpected given the greater potential harm posed by long-lived high LET radionuclidic impurities. Manufacturers that can ensure the production of therapeutically useful radionuclides with the following three characteristics are at a significant advantage entering the FDA review process and, subsequently, in the deployment of their products in the medical technology markets: (1) high radionuclidic purity; (2) high chemical purity; and (3) predictable radionuclide generator behavior.
The need to ensure high radionuclidic purity stems directly from the hazards associated with the introduction of long-lived or high energy radioactive impurities into a patient, especially if the biolocalization and body clearance characteristics of the radioactive impurities are unknown. Radionuclidic impurities pose the greatest threat to patient welfare, and such contaminants are the primary focus of clinical quality control measures that attempt to prevent the administration of harmful, and potentially fatal, doses of radiation to the patient.
Chemical purity is vital to a safe and efficient medical procedure because the radionuclide must generally be conjugated to a biolocalization agent prior to use. This conjugation reaction typically relies on the principles of coordination chemistry wherein an illustrative cationic radionuclide is chelated to a ligand that is covalently attached to a biolocalization agent. In a chemically impure sample, the presence of ionic impurities can inhibit this conjugation reaction resulting in a substantial quantity of radionuclide not bound to the biolocalization agent. Therapeutic radionuclides not associated with a biolocalization agent not only pose a health concern if administered, but represent an inefficient use of both the radionuclide and the costly biolocalization agent.
Given the preeminent position of technetium-99m (99mTc) in diagnostic nuclear medicine and the simple and effective operation of the conventional 99mTc generator (FIG. 1), the logic and design of this radionuclide generator have become the industry standard for nuclear medicine. This conventional radionuclide generator is widely used in diagnostic nuclear medicine where the decay schemes involve less energetic radionuclides and, subsequently, radiolytic degradation of the support matrix is inconsequential.
Conversely, radiotherapeutic nuclides have a high LET that causes significant damage to the support material that is used in the purification process and is therefore responsible for the purity of the product. The adverse effects from radiation damage have frequently been observed with radiotherapeutic nuclides [see, Hassfjell et al., Chem. Rev. 2001, 101:2019-2036; Gansow et al., in Radionuclide Generators: New Systems for Nuclear Medicine Applications, Knapp, Jr. et al. Eds., American Chemical Society: Washington, D.C., 1984, pp 215-227; Knapp, F. F., Jr.; Butler, T. A., Eds. Radionuclide Generators: New Systems for Nuclear Medicine Applications; American Chemical Society: Washington, D.C., 1984; Dietz et al., Appl. Radiat. Isot. 1992, 43:1093-1101; Mirzadeh et al., J. Radioanal. Nucl. Chem. 1996, 203:471-488; Lambrecht et al., Radiochim. Acta 1997, 77:103-123; and Wu et al., Radiochim. Acta 1997, 79:141-144] and can degrade the generator performance and separation efficiency to a point where patient safety is compromised.
The same LET that makes α- and β1−-emitting nuclides potent cytotoxic agents for cancer therapy also introduces many unique challenges into the production and purification of these radionuclides for use in medical applications. Foremost among these challenges is the radiolytic degradation of the support material that occurs when the conventional generator methodology of FIG. 1 is used with high LET radionuclides. [See, Hassfjell et al., Chem. Rev. 2001, 101:2019-2036; Gansow et al., in Radionuclide Generators: New Systems for Nuclear Medicine Applications; Knapp, Jr. et al. Eds., American Chemical Society: Washington, D.C., 1984, pp 215-227; Knapp, F. F., Jr.; Butler, T. A., Eds. Radionuclide Generators: New Systems for Nuclear Medicine Applications; American Chemical Society: Washington, D.C., 1984; Dietz et al., Appl. Radiat. Isot. 1992, 43:1093-1101; Mirzadeh et al., J. Radioanal. Nucl. Chem. 1996, 203:471-488; Lambrecht et al., Radiochim. Acta 1997, 77:103-123; and Wu et al., Radiochim. Acta 1997, 79:141-144.] Radiolytic degradation of the generator support material can result in: (1) compromised radionuclidic purity (e.g., the support material may release parent radionuclides to the eluate: termed “breakthrough”); (2) diminished chemical purity (e.g., radiolysis products from the support matrix may contaminate the daughter solution); (3) low yields of daughter radionuclides (e.g., α-recoil could force the radionuclides into stagnant regions of the support making them less accessible to the stripping eluent); (4) decreases in column flow rates (e.g., fragmentation of the support matrix may create fine particles that clog the chromatographic bed); and (5) erratic performance (e.g., variability in product purity, non-reproducible yields, fluctuating flow rates, and the like).
As discussed above, the use of high LET α- and β1−-emitting radiation holds great promise for the therapy of micrometastatic carcinoma and certain tumor masses, but realization of the full potential of targeted radiotherapy requires the development of ample supplies and reliable generators for high LET radionuclides. [See, Geerlings et al., U.S. Pat. No. 5,246,691, 1993; Whitlock et al., Ind. Eng. Chem. Res. 2000, 39:3135-3139; Hassfjell et al., Chem. Rev. 2001, 101:2019-2036; Imam, Int. J. Radiation Oncology Biol. Phys. 2001, 51:271-278; and McDevitt et al., Science 2001, 294:1537-1540.] One candidate α-emitter proposed for use in cancer therapy is bismuth-213 (213Bi), [see, Geerlings et al., U.S. Pat. No. 5,246,691, 1993; Hassfjell et al., Chem. Rev. 2001, 101:2019-2036; and Imam, Int. J. Radiation Oncology Biol. Phys. 2001, 51:271-278], which forms as part of the uranium-233 (233U) decay chain shown in FIG. 2.
The commercial deployment of 213Bi is expected to involve shipment of the 10.0 day half-life 225Ac parent to the nuclear pharmacy for use as the generator source material. Examination of FIG. 3 shows that 225Ra, with a half-life of 14.9 days, also appears to be a suitable source material for use in the nuclear pharmacy; however, trace 224Ra arising from 233U nucleogenesis side reactions contaminates the 225Ra. Radium-224 introduces very unfavorable radionuclidic contaminants that collectively prohibit the use of 225Ra as the source material. Actinium-225 is a unique member of the 225Ra decay chain and does not appear as a 224Ra daughter, and thus 225Ac represents the best source material for the production of 213Bi in the nuclear pharmacy. Key radionuclidic impurities in the production of 213Bi include the relatively long-lived 225Ac parent and, to a lesser extent, the trace 225/224Ra that could potentially arise from inefficient separations of 225Ac from 225/224Ra and 229/228Th.
After separation from its radiogenic relatives in the nuclear pharmacy, the 213Bi is typically conjugated to a biolocalization agent using coordination chemistry alluded to previously. The cyclic and acyclic polyaminocarboxylates are among the most widely used chelating moieties tethered to biolocalization agents [see, Hassfjell et al., Chem. Rev. 2001, 101:2019-2036; Jurisson et al., Chem. Rev. 1993, 93:1137-1156; Schwochau, Angew. Chem. Int. Ed. Eng. 1994, 33:2258-2267; and Anderson et al., Chem. Rev. 1999, 99:2219-2234] and, consequently, the pH range 4-8 is preferred to promote efficient radioconjugation and to minimize chemical attack (e.g., denaturation, hydrolysis, etc.) of the biolocalization agent. An ideal generator would thus produce 213Bi in dilute acid or in a physiologically acceptable buffer solution that does not contain ligands that can interfere with the radioconjugation reaction such as I1−, chelating agents, and the like.
With an understanding that the radionuclide generator requires an initial separation of a hard Lewis acid Ac3+ ion from a soft Lewis acid Bi3+ ion, the differing Lewis acidities and the concomitant difference in stabilities of the halide ion complexes of Ac3+ and Bi3+ provides a chemical means to be exploited for the separation. By example, the logarithm of the overall complex formation constants (log βMHL) for BiCl41− is log β104=6.4 at μ=1.0 and 25° C., whereas only the log β101=−0.1 is reported for the formation of AcCl+ and CeCl+. [See, Martell et al., “Critically Selected Stability Constants of Metal Complexes: Database Version 4.0,” NIST; Gaithersburg, Md., 1997.]
Given the similarity in the weak complex formation constants of the first Cl1− complexes (i.e., log β101) of Ac3+ and Ce3+ and the approximate similarity in their six-coordinate ionic radii (i.e., Ce3+=1.01 Å and Ac3+=1.12 Å) [see, Shannon, Acta Crystallogr., Sect. A 1976, 32:751-767], Ce3+ was used as a chemical analog for Ac3+ in the initial stages of generator development discussed hereinafter. Cerium-139 also possesses a γ-emission that permits direct assay, rather than relying on the characteristic 218 keV γ-emission of 221Fr to indirectly monitor 225Ac behavior. (The preponderance of α- and β1−-emissions of the 225Ac daughters makes liquid scintillation (LSC) counting impractical for these studies.)
The propensity of Bi(III) to form stable anionic complexes with halide ions suggests that anion-exchange resins or membranes can be effective for the separation of BiX41− (X=Cl1−, Br1−, or I1−) from Ac(III), [see, Diamond et al., in Ion Exchange; Marinsky Ed., Marcel Dekker: New York, 1966, Vol. 1, pp 277-351] and several authors have utilized such an approach. [See, Hassfjell et al., Chem. Rev. 2001, 101:2019-2036; Bray et al., U.S. Pat. No. 5,749,042, 1998; Egorov et al., U.S. Pat. No. 6,153,154, 2000; and Bray et al., Ind. Eng. Chem. Res. 2000, 39:3189-3194.] Recent studies have employed anion-exchange membranes in a manual 213Bi(III) purification technology [see, Bray et al., U.S. Pat. No. 5,749,042, 1998; and Bray et al., Ind. Eng. Chem. Res. 2000, 39:3189-3194] that was subsequently automated. [See, Egorov et al., U.S. Pat. No. 6,153,154, 2000.]
Those membrane technologies relied on the use of a single anion-exchange membrane to retain 213Bi(III) from 0.5 M HCl, while passing its radiogenic relatives. After a gas flush of the membrane and its associated housing, as much as 2-3 percent of the 225Ac(III) parent remained and was necessarily removed by a 0.005 M HCl rinse. Because of the low acid concentration, this rinse solution containing 225Ac(III) could not be directed to the 225Ac(III) source vessel, and resulted in a net depletion of 225Ac from the generator system. The 213Bi(III) was subsequently stripped from the anion-exchange membrane using 0.1 M NaOAc at pH=5.5, which eluted only 88 percent of the 213Bi(III) in 4 mL of strip solution. The volume of solution in which the 213Bi(III) was recovered in these tests is near the upper limit of acceptability, as the subsequent radioconjugation reactions and other operations that precede clinical administration typically dilute the 213Bi even further, resulting in a low specific radioactivity sample.
The radionuclidic purity of the 213Bi purified using the above-described anion-exchange membrane technology is poor, with a reported decontamination factor (DF) of 213Bi from 225Ac of only about 1400. This DF corresponds to about 21 μCi (or 4.7×107 disintegrations per minute) of 225Ac contaminating a single 30 mCi patient dose of 213Bi. Such a quantity of the long-lived 225Ac parent is unacceptable from patient safety and dosimetry considerations, and the poor DF ultimately leads to unacceptable losses of 225Ac that shorten the 213Bi generator duty cycle.
An alternative separation to conventional anion exchange centers on the observation that the BiX41− anion can be extracted from hydrohalic acid aqueous phases into a variety of polar diluents [see, Rogers et al., in Solvent Extraction in the Process Industries, Proceedings of ISEC'93; Logsdail et al. Eds., Elsevier Applied Science: London, 1993, Vol. 3, pp 1641-1648] and into solvents containing neutral organophosphorus extractants (i.e., phosphine oxides, phosphinates, phosphonates, and phosphates). [See, Sekine et al., Solvent Extraction Chemistry; Marcel Dekker: New York, 1977.] By example, solvent extraction using tri-n-butyl phosphate has been shown to partition [H3O][TcO4] (TcO41− is a large polarizable anion resembling BiX41−) to the organic phase and various platinum group metal halides (e.g., PdCl42−) have been extracted by various alkylphosphine oxide organic phases.
The thermodynamic drivers for BiX41− extraction from dilute hydrohalic acid media into neutral organophosphorus extractant systems involve: (1) the salvation of the hydronium cation (H3O+) by hydrogen-bonding interactions with the strongly Lewis basic phosphoryl oxygen donors of the neutral organophosphorus extractants and (2) the salvation preferences of the BiX41− anion that encounters a more thermodynamically favorable salvation environment in the polar organic phase. In practice, stripping of Bi(III) from such systems can be accomplished by raising the pH value (i.e., consuming H3O+) and/or by increasing the halide concentration leading to formation of BiX52− and/or BiX63− complexes that report to the aqueous phase.
The above anionic membrane technology notwithstanding, bismuth-213 is presently obtained for use by elution from a conventional generator in which the relatively long-lived (i.e., 10.0 day) actinium-225 (225Ac) parent is retained on an organic cation-exchange resin, while the 213Bi is eluted with HCl [see, Geerlings et al., U.S. Pat. No. 5,246,691, 1993; Lambrecht et al., Radiochim. Acta 1997, 77:103-123; and Mirzadeh, Appl. Radiat. Isot. 1998, 49, 345-349] or mixtures of Cl− and I−. [See, Geerlings et al., U.S. Pat. No. 5,246,691, 1993; Lambrecht et al., Radiochim. Acta 1997, 77:103-123; Mirzadeh, Appl. Radiat. Isot. 1998, 49, 345-349; Geerlings, U.S. Pat. No. 5,641,471, 1997; and Geerlings, U.S. Pat. No. 6,127,527, 2000.]
This generator strategy suffers from the adverse effects of radiolytic degradation outlined above, and the use of I1− to facilitate effective stripping inhibits the conjugation of 213Bi to biolocalization agents. The Bi—I bond possesses considerable covalent character and the complex formation constants for I1− complexes of Bi3+ are large, [see, Martell et al., “Critically Selected Stability Constants of Metal Complexes: Database Version 4.0,” NIST; Gaithersburg, Md., 1997] suggesting that I1− can effectively compete with the polyaminocarboxylate chelating moieties of the biolocalization agent. In order for 213Bi to be successfully deployed in cancer therapy, new generator technologies are needed to enable the reliable production of 213Bi of high radionuclidic and chemical purity.
A variety of organic sorbents, most notably the conventional cation- and anion-exchange resins, have been proposed for use in nuclear medicine generators [see, Gansow et al., in Radionuclide Generators: New Systems for Nuclear Medicine Applications, Knapp, Jr. et al. Eds., American Chemical Society: Washington, D.C., 1984, pp 215-227; Mirzadeh et al., J. Radioanal. Nucl. Chem. 1996, 203:471-488; Lambrecht et al., Radiochim. Acta 1997, 77:103-123; Geerlings, U.S. Pat. No. 5,641,471, 1997; Geerlings, U.S. Pat. No. 6,127,527, 2000; and Molinski, Int. J. Appl. Radiat. Isot. 1982, 33:811-819] due to the well documented chemical selectivity [see, Diamond et al., in Ion Exchange, Marinsky, J. A., Ed.; Marcel Dekker: New York, 1966; Vol. 1, pp 277-351; and Massart, “Nuclear Science Series, Radiochemical Techniques: Cation-Exchange Techniques in Radiochemistry,” NAS-NS 3113; National Academy of Sciences; 1971] and the widespread availability of these materials.
Unfortunately, organic-based ion-exchange resins frequently fail or are severely limited in applications using the conventional generator logic depicted in FIG. 1, and typically do so at radiation levels far below those needed for therapeutic use. By example, polystyrene divinylbenzene copolymer-based cation-exchange resins are used in a generator for the α-emitter 212Bi, but such materials are limited to approximately two-week duty cycles for 10-20 mCi generators. Radiolytic degradation of the chromatographic support, primarily by the high LET α radiation, reportedly leads to diminished flow rates, reduced 212Bi yields, and breakthrough of the 224Ra parent. [See, Mirzadeh et al., J. Radioanal. Nucl. Chem. 1996, 203:471-488.] Similarly, a 213Bi generator employing an organic cation-exchange resin was limited to a shelf life of approximately one week at an activity level of 2-3 mCi of the α-emitting 225Ac parent. [See, Mirzadeh et al., J. Radioanal. Nucl. Chem. 1996, 203:471-488 and Lambrecht et al., Radiochim. Acta 1997, 77:103-123.]
Over time, this conventional generator gave reduced yields of 213Bi, poor radionuclidic purity, and unacceptably slow column flow rates. [See, Mirzadeh et al., J. Radioanal. Nucl. Chem. 1996, 203:471-488 and Lambrecht et al., Radiochim. Acta 1997, 77:103-123.] The useful deployment lifetime of the 213Bi generator as well as the amount of 213Bi activity that can be produced is severely limited by the support materials suitable for use with the conventional generator methodology. [See, Hassfjell et al., Chem. Rev. 2001, 101:2019-2036; and Mirzadeh, Appl. Radiat. Isot. 1998, 49:345-349.]
Inorganic materials have been used in α-particle generators and are not immune to radiolytic degradation. Several early versions of the α-emitting 212Bi generator [see, Gansow et al., in Radionuclide Generators: New Systems for Nuclear Medicine Applications, Knapp, Jr. et al. Eds., American Chemical Society: Washington, D.C., 1984, pp 215-227; and Mirzadeh, Appl. Radiat. Isot. 1998, 49:345-349] used inorganic titanates to retain the long-lived thorium-228 parent, from which the radium-224 (224Ra) daughter elutes and is subsequently sorbed onto a conventional cation-exchange resin. Over time the titanate support succumbed to radiolytic degradation, creating fine particulates that forced separations to be performed at elevated pressures.
The so-called hybrid sorbents can be subdivided into extraction chromatographic materials and engineered inorganic ion-exchange materials. Most of the published applications of hybrid materials have used extraction chromatography, whereas the preparation and use of engineered inorganic materials is a more recent phenomenon. Extraction chromatography overcomes the poor ion selectivity and slow partitioning kinetics of inorganic materials by using solvent extraction reagents physisorbed to an inert chromatographic substrate. [See, Dietz et al., in Metal Ion Separation and Preconcentration: Progress and Opportunities; Bond et al., Eds., American Chemical Society: Washington, D.C., 1999; Vol. 716, pp 234-250.]
The radiolytic stability of extraction chromatographic supports is improved when the inert substrate is an amorphous inorganic material such as silica, with the most profound results reflected as sustainable flow rates over the generator duty cycle. Such “improved” radiolytic stability is deceptive, however, as the fundamental chemical reactions underlying the parent/daughter separation still involve molecules constructed from an organic framework that remains susceptible to radiolytic degradation. Likewise, organic-based chelating moieties have been engineered into inorganic ion-exchange materials to improve analyte selectivity, but such functionalities continue to suffer the effects of radiolysis.
Preliminary reports using hybrid sorbents as conventional generator supports in the production of 213Bi have appeared. [See, Hassfjell et al., Chem. Rev. 2001, 101:2019-2036; Lambrecht et al., Radiochim. Acta 1997, 77:103-123; Wu et al., Radiochim. Acta 1997, 79:141-144; and Horwitz et al., U.S. Pat. No. 5,854,968, 1998.] Initial improvements centered on sorption of the 225Ac parent of 213Bi on Dipex® Resin, an inert silica-based support to which a chelating diphosphonic acid diester is physisorbed that is available from Eichrom Technologies, Inc., Darien, Ill. The silica substrate exhibits greater radiolytic stability than the previously employed organic resins; however, radiolytic damage (i.e., discoloration) was observed surrounding the narrow chromatographic band in which the 225Ac parent was loaded, ultimately leading to breakthrough of the 225Ac parent. [See, Lambrecht et al., Radiochim. Acta 1997, 77:103-123; and Wu et al., Radiochim. Acta 1997, 79:141-144.]
An incremental improvement in the above generator centered on reducing the radiation density by dispersing the 225Ac radioactivity over a larger volume of the chromatographic support, which is achieved by loading the Dipex® Resin with 225Ac in a batch mode rather than in a narrow chromatographic band. [See, Hassfjell et al., Chem. Rev. 2001, 101:2019-2036; and Wu et al., Radiochim. Acta 1997, 79:141-144.] Unfortunately, this batch loading process is awkward and the Dipex® Resin still suffers from radiolytic degradation of the chelating diphosphonic acid diester upon which the separation efficiency relies.
The ideal radionuclide generator technology should offer operational simplicity and convenience as well as reliable production of near theoretical yields of the desired daughter radionuclide having high chemical and radionuclidic purity. As deployed for diagnostic radionuclides, the conventional generator technology shown in FIG. 1 generally meets several of these criteria, although purity and yield have been observed to fluctuate. [See, Molinski, Int. J. Appl. Radiat. Isot. 1982, 33:811-819; and Boyd, Acta 1982, 30:123-145.]
The conventional generator is poorly suited to systems involving the high LET radionuclides useful in therapeutic nuclear medicine. The conventional generator methodology is thus not universally acceptable for all radionuclides, especially those targeted for use in therapeutic nuclear medicine. Despite industry preferences for the conventional generator depicted in FIG. 1, the fundamental limitations imposed by radiolytic degradation of the support medium by high LET radioactivity cannot be ignored. The severity of these limitations coupled with the ultimate liability of compromised patient safety argue for the development of alternative generator technologies for therapeutically useful radionuclides.
A shift in the fundamental principles governing generator technologies for therapeutic nuclides is further supported by the fact that the inadvertent administration of the long-lived parents of high LET therapeutic radionuclides would compromise the patient's already fragile health; potentially resulting in death. Because the conventional generator strategy depicted in FIG. 1 relies on long-term storage of the parent radionuclide on a solid support that is constantly subjected to high LET radiation, no assurances can be made regarding the radionuclidic and chemical purity of the daughter radionuclide over a typical 14-60 day generator duty cycle.
The inevitable and unpredictable adverse effects of radiolytic degradation of chromatographic supports by the high LET α-emitting descendents of 225Ac pose enormous challenges to the development of reliable and efficient 213Bi radionuclide generators. Any damage to the support material in the conventional generator methodology compromises the separation efficiency, potentially resulting in breakthrough of the parent radionuclides and to a potentially fatal dose of radiation if administered to the patient.
The occurrence of such a catastrophic event can be minimized by the quality control measures integrated into nuclear pharmacy operations, but any lack of safe, predictable generator behavior represents a major liability to the nuclear pharmacy, hospital, and their respective shareholders. The invention described hereinafter provides an alternative technology for the production of 213Bi using a multicolumn selectivity inversion generator that reliably produces near theoretical yields of 213Bi of high radionuclidic and chemical purity, minimizes the likelihood of breakthrough of parental radionuclide, and provides for long-term storage of the parent radionuclide separate from the separation media.